Allergan's submissions
539 On the face of it, the studies and other evidence relied on by Self Care amount to a substantial foundation for a representation that the respective products significantly reduce the appearance of wrinkles. Mr Williams gave evidence in respect of each of the products and confirmed that in his view, and on the basis of the formulations of the products and the studies relied on, the products would be expected to significantly reduce the appearance of wrinkles. Dr Haley, in his reports, raised certain queries and criticisms of the studies and in some respects he had a different view of the likely impact of some of the ingredients of some of the products. The disagreements between Mr Williams and Dr Haley were reduced during the process of concurrent examination. Moreover, only some of the issues raised by Dr Haley in his reports were taken up by Allergan in its submissions, written and oral, in support of its case that Self Care's efficacy representations are misleading or deceptive.
540 As a practical matter, I only intend dealing with the arguments made by Allergan as to why the studies and other evidence relied on by Self Care do not amount to reasonable grounds for the representations. In the light of Allergan apparently not relying on other points, queries and criticisms raised by Dr Haley, I do not intend dealing with those matters if they have not been raised or relied on by Allergan.
541 Allergan makes essentially five arguments against a conclusion that the above studies, and other evidence, amount to "reasonable grounds" for the representations.
542 Allergan's principal argument is that none of the studies makes a head-to-head comparison of the visible results of the use of Botox with the use of Self Care's products. It submits that it is not to the point whether or by how much Self Care's products achieve an improvement in the appearance of expression lines generally. Allergan also submits that it is not possible to make a comparison between a skincare product that is topically applied, such as Self Care's products, with Botox, which is injected into the muscle, given the differing modes of action and the number of variables.
543 Allergan relies, in particular, on Reckitt Benckiser (Australia) in which Gleeson J (at [307]-[308]) reasoned that because none of the studies that were relied on in that case was directed to a comparison of the two products, Nuromol and Maxigesic, they did not provide an adequate foundation for the representation that one tablet of Nuromol provides equivalent or superior pain relief to two tablets of Maxigesic. Her Honour's judgment was upheld on appeal, in AFT Pharmaceuticals, where it was reasoned that one real difficulty for AFT in establishing that the primary judge erred in evaluating the scientific evidence was that there was no scientific study which directly related to the efficacy of Maxigesic or Nuromol at their respective recommended daily doses - "None of the scientific studies provided a direct, head-to-head comparison of the efficacy of analgesic products with the same levels of paracetamol/ibuprofen as Maxigesic and Nuromol at maximum daily doses": at [104].
544 There are a few matters to be observed in considering the application of the reasoning in that case to the present case. First, the representation at issue was a measurable quantitative comparative representation, i.e., that the one tablet was at least twice as good as the other. The representations in the present case, with one exception, are quite different, namely that the efficacy of the relevant products produces similar results in the appearance of the reduction of wrinkles. That representation is not exact or quantifiable in its comparative statement.
545 Second, Gleeson J's conclusion relied on by Allergan that because there was no head-to-head study of the two products the comparative statement could not be justified was not stated as a principle to be applied across all cases involving comparative claims, and it was not adopted in such terms by the Full Court in the appeal. Inherent in the reasoning of the Full Court is the possibility that the comparative representation could have been justified by scientific studies that were not head-to-head studies of the respective products at the relevant doses. The conclusion was that where some studies favoured the contentions of one side of the case and other studies favoured the contentions of the other side of the case (at [105]), the absence of an applicable head-to-head study created a "real difficulty" in establishing a foundation for the representation: at [104]. The Full Court did not reason that in the absence of a head-to-head study it would be impossible to establish a proper foundation. In this case there is no evidence of opposing studies giving weight to contentions of Allergan that Self Care's products do not have the effects as represented.
546 Given those differences, I do not accept the submission that the absence of head-to-head comparative studies between Self Care's products and the Botox product is on its own a basis for finding that Self Care's efficacy representations are without reasonable grounds.
547 The exception that I have referred to is the representation that the Night (tube) product "delivers the results of … a Botox injection in four weeks". That representation, as I have said, is exact both as to the comparable results and the time period. As will be seen, the absence of a head-to-head comparison in that case is significant.
548 In view of my conclusion that the representations that are made by the impugned statements say nothing about the mechanism or mode of action of Self Care's products, Allergan's submission, and Ms Cain's opinion, that those products cannot be compared with Botox because they have different mechanisms or modes of action must be rejected. The statements and hence the representations concern the apparent outcomes of the use of the products, i.e., how the skin appears after having used the products. It says nothing about what is actually happening to the skin or how any effects are achieved. The question is whether the claim that the products achieve a similar reduction in the appearance of wrinkles is well-founded.
549 Allergan's second argument is that some of the studies make highly speculative claims about the efficacy of the products, particularly with reference to the mechanism of action. For example, Studies 1 and 2, in respect of Active A, speculate that the mechanism of action includes effects at the level of the dermis, whereas with reference to another study, referred to as the Kraeling article, Active A would not penetrate to the level of the dermis. The expert witnesses agreed that the peptides would not penetrate to the dermis. The expert witnesses were also in agreement that the mechanism of action of the active peptides in vivo is as a scientific matter not known or explained.
550 However, as I have identified, the question is not about the mechanism of action of the ingredients, but rather the aesthetic outcome. Studies 1 and 2 reported positively on the effect that Active A has on reducing the appearance of wrinkles. They did so by the use of an accepted method of measuring wrinkles known as confocal profilometry which involves taking silicone rubber impression mouldings of a face and then analysing them using a confocal microscope which produces data which is then processed using a digital imaging program on a computer. Study 1, being a supplier's product brochure on Active A, reports on the results of a number of studies of which Study 2 is one.
551 Allergan's third argument is that it is not possible to attribute the positive visual effects achieved by the active ingredients of Self Care's products to the identified "actives" or peptides in those products. It submits that that is because, in relation to the peptides:
(1) only a very small amount of the peptide is used ([redacted until 6 June 2021]% of the product total in most cases);
(2) only a very small amount may get into the viable epidermis (of the order of 0.01% of the peptide applied);
(3) when used in a concentration of [redacted until 6 June 2021]%, only 0.0000005% of the product total or 0.5 ppm would penetrate to the viable epidermis;
(4) the peptides do not penetrate to the dermis, where the muscles or the nerves relevantly operate; and
(5) there are so many other skin conditioning agents in the products (except Boost which is [redacted until 6 June 2021]% water), that they would swamp any effect that reduces the appearance of wrinkles.
552 There are essentially two components to this argument that the peptides in the product do not produce a significant visual effect. The one is that they are in too low a concentration to be effective, and the other is that any effect that is seen is because of moisturising ingredients rather than the peptides.
553 In reliance on the Kraeling article, Dr Haley initially did not attribute any efficacy to the peptide. The Kraeling study showed that the peptide acetyl hexapeptide-8, which was used by both experts as a suitable proxy for all of the peptides under consideration, penetrated to the viable epidermis of human skin in vitro to the extent of 0.01%. From this, Dr Haley concluded that the peptide would not have any significant efficacy in reducing the appearance of wrinkles in vivo.
554 However, Study 2, demonstrates a significant visual effect. Mr Williams accepted that that was a cosmetic effect and not therapeutic because of the level at which it operates, but he was not challenged on there being a positive visual effect on the appearance of wrinkles.
555 The aim of Study 2 was to evaluate the macro-roughness of human skin replicas in silicone to determine the wrinkle reduction efficacy of Active A compared to a placebo cream. The macro-roughness of the silicone replica, which corresponded to the eye contour area, was obtained from 17 volunteers for the test cream and from 10 volunteers for the placebo cream. The treatment lasted four weeks and samples obtained before treatment started and after 28 days were taken. Skin roughness was measured by confocal profilometry across multiple parameters. The study concluded that the test product containing Active A reduced wrinkles by about 34% on average, which is significant compared to the placebo cream which reduced wrinkles by about 3% on average. The reduction in the depth of the wrinkles was about 63% in some instances.
556 Dr Haley challenged these results on the basis that the results for the placebo group (i.e., little or no improvement in the appearance of reduction of wrinkles) were not consistent with his expectations of a product having the ingredients shown in the formulation of the placebo, which included certain moisturising ingredients, in particular glycerin at 2.4%. He said that it is quite feasible to him that the performance of the placebo cream formulation with an additional 0.005% of the peptide coming from Active A (i.e., the test product) could be totally coming from the placebo base formulation.
557 However, Dr Haley accepted that he had done no tests on the performance of the placebo cream, i.e., he was speaking merely from expectation, and he was unable to explain why the test cream and the placebo cream produced markedly different results which he accepted were statistically significant. He accepted that the use of the placebo was designed to exclude the possibility that the results of the active product are attributable to the moisturisers in which it was carried.
558 On the question of the concentration of the active ingredient in the product, Dr Haley accepted that in the absence of testing one cannot make an assumption that any particular ingredient has no effect at any particular concentration, even at very low levels such as 0.1%. Different ingredients will have effect at different concentrations, which is known as the dose response correlation. Mr Williams explained that it is well-known in the cosmetic and therapeutic industries that "the dose makes the activity", by which I understood him to mean that some substances (such as botulinum toxin as an example) have effect at extremely low dosages and others have effect only at very high dosages, and everything in between. It depends on the dose response correlation for the particular ingredient.
559 Mr Williams explained that it can be misleading to look at the possible effect of an active ingredient in percentage terms as that neglects to take account of the activity of the actual molecule which may be very active, as in the case of peptides. Thus the frequent application of a product with a very low concentration of the peptide may nevertheless deliver a sufficient dosage of the peptide over time to have an active effect.
560 Ultimately Dr Haley accepted, as I do, that Study 2 demonstrates that the peptides are responsible for the improved performance of the test product over the placebo.
561 Allergan's arguments that the observed positive results cannot be attributed to the active ingredient, which I have rejected above, are applicable to Studies 2, 6, 7 and 11.
562 Allergan's fourth argument, with reference to the ICH Harmonized Tripartite Guideline for the Structure and Content of Clinical Study Reports (1995), is that ignoring patients who dropped out of Study 2 and drawing conclusions based only on patients who completed a study can be misleading and can introduce bias. It submits that there is a danger in dropping patients with available data from analysis because of poor compliance and eligibility or any other reasons. It submits that an analysis using all available data should be carried out for all studies intended to establish efficacy.
563 The ICH is the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use. The ICH Guideline includes the following paragraphs relied on by Allergan:
11.4.2.2 Handling of Dropouts or Missing Data
There are several factors that may affect dropout rates. These include the duration of the study, the nature of the disease, the efficacy and toxicity of the drug under study, and other factors that are not therapy related. Ignoring the patients who dropped out of the study and drawing conclusions based only on patients who completed the study can be misleading. A large number of dropouts, however, even if included in an analysis, may introduce bias, particularly if there are more early dropouts in one treatment group or the reasons for dropping out are treatment or outcome related. …
11.4.2.6 Use of an "Efficacy Subset" of Patients
Particular attention should be devoted to the effects of dropping patients with available data from analyses because of poor compliance, missed visits, ineligibility, or any other reason. As noted above, an analysis using all available data should be carried out for all studies intended to establish efficacy, even if it is not the analysis proposed as the primary analysis by the applicant. In general, it is advantageous to demonstrate robustness of the principal trial conclusions with respect to alternative choices of patient populations for analysis. Any substantial differences resulting from the choice of patient population for analysis should be the subject of explicit discussion.
564 Study 2 records that "about 20 volunteers were chosen for each product" (i.e., for the test cream and the placebo cream), but some of them did not complete the study satisfactorily so they were not included in the analysis of the results obtained. I infer that three volunteers dropped out from the test group and 10 dropped out from the control group. I note that Dr Haley drew the same conclusion.
565 Dr Haley said that it was a matter of concern that 10 of the placebo test subjects had dropped out and that no reasons were recorded. However, he accepted that the study was statistically significant and he failed to explain why the absence of the information about why 10 participants had dropped out would make the study unreliable. Ultimately, he accepted in cross-examination that that matter alone would not constitute a tipping point such as to cause an otherwise reliable study to be unreliable.
566 Insofar as the ICH Guideline is concerned, it describes its objective as being to allow the compilation of a single core clinical study report acceptable to all regulatory authorities of the ICH regions. Such a clinical study report would be of an individual study of any therapeutic, prophylactic or diagnostic agent conducted in patients. By its own terms, and it was accepted by Dr Haley, the ICH Guideline did not apply to unregulated cosmetics. Further, in its introduction it states that depending on the nature and importance of the study, a less detailed report might be appropriate. Dr Haley was unable to explain why in the case of Study 2, to which the ICH Guideline did not apply, it was inappropriate to not include the reasons why participants dropped out. Since the data measurements were at the commencement of the trial and at its end, clearly there was no relevant data to record in respect of any participant who dropped out before the twenty-eighth day.
567 Mr Williams was cross-examined with reference to the ICH Guideline. He explained that it is not generally applied to cosmetic products. He offered the plausible explanation that 10 out of the original 20 participants in the placebo group may have dropped out because they were not noticing any reduction in the appearance of wrinkles. If that is the reason that they dropped out, that does not detract from the reliability of the study. He said that in his view the difference between the placebo and the test product is sufficient based on the standard deviation in the remaining test subjects to still be reliable.
568 In the circumstances, I do not accept the criticism of Study 2 based on the number of drop-outs and the absence of any recorded reason for them dropping out. I accept that the study offers a reasonable foundation to the claim that Active A produces a significant reduction in the appearance of wrinkles over a 28-day period of application.
569 Allergan's fifth argument was made by Dr Haley. It was not put squarely in written or oral submissions by Allergan but I deal with it here as an argument advanced by Allergan for the sake of completeness and because there may have been hints at it in submissions. It is what Self Care in its submissions characterised as an "extrapolation issue". The argument is that one cannot necessarily apply the results of studies of an active ingredient to the performance of a product containing it. It arises because most of the studies that Self Care relies on are studies of the efficacy of the active ingredients in product formulations that may not be exactly the same as Self Care's formulations.
570 Mr Williams explained that in Australia cosmetic manufacturers tend to use the results of studies on ingredients when formulating their products. The extrapolation is justified where the concentration of the active ingredient in the product is at the same level (or greater) as in the test and if there is nothing in the product which will impair the result that is shown for the active ingredient it is accepted. Although that is not the approach with respect to therapeutics, presumably because of critical safety issues in relation to therapeutic substances which is what justifies their strong regulation, it is the case with respect to cosmetics because of the prohibitive cost relative to the size of the Australian market to conduct studies on each product itself.
571 Dr Haley accepted that the concentrations of the active ingredients in each of the Self Care products, save for the Boost product prior to a correction in its formulation in August 2018, was the same as in the respective studies relied on by Self Care. He also did not identify any component in any of the products that would impair the performance of the peptides in the product formulations.
572 In the result, I accept that the results of each of Studies 3, 4, 6-10 and 13, to which this extrapolation issue applies, can be extrapolated to the respective products.